Fundus Changes Associated With Congenital Hypertrophy of the Retinal Pigment Epithelium Line Chamot, M.D., Leonidas Zografos, M.D., and Giorgio Klainguti, M.D.
The clinical characteristics and follow-up changes of 64 patients with solitary congenital hypertrophy of the retinal pigment epithelium were studied. Thirty-five of the patients were followed up for one to 14 years with serial fundus photography. Progressive increase of the hypopigmented part of the lesion was observed in 29 of the 35 patients who were followed up (82.8%). An enlargement of the lesion was seen in 26 of the 35 patients (74.3%). Two additional changes, that is, pigmented areas adjacent to congenital hypertrophy of the retinal pigment epithelium and linear streaks of the pigment epithelium, were documented. Pathogenetic mechanisms for the development of these changes remain unknown. CONGENITAL HYPERTROPHY of the retinal pigment epithelium is a dark gray or black, flat, round or oval lesion of the retinal pigment epithelium, with well-demarcated, smooth or scalloped margins, found usually during routine fundus examination. Smaller lesions are mostly uniformly pigmented, whereas larger lesions show various degrees of depigmentation, often with punched-out lacunae. Congenital hypertrophy of the retinal pigment epithelium is frequently surrounded by a marginal halo of depigmentation that is internal to a darker rim, which together produce a double outline."!' Congenital hypertrophy of the retinal pigment epithelium was first described by Reese and jones' in 1956 as benign melanoma. The hypertrophic nature of the pigment epithelium cells in these lesions was demonstrated by Kurz
Accepted for publication Oct. 28, 1992. From the University Eye Clinic, Lausanne, Switzerland. Reprint requests to Line Chamot, M.D., University Eye Clinic, Av. de France 15, CH-1004 Lausanne, Switzerland.
and Zimmerman" in 1962 and Buettner" in 1974. The term" congenital hypertrophy of the retinal pigment epithelium" was introduced by Buettner and has become widely accepted. Gass" recently proposed a new classification of focal congenital anomalies of the pigment epithelium and suggested that "solitary melanotic nevi of the retinal pigment epithelium" would be a more appropriate term. At first, it was thought that this lesion does not show progressive changes. I Later, Buettner" described an increase of the hypopigmented part, and Norris and Cleasby" described a concentric enlargement. Additional studies confirmed these findings. 5' 9,14,15 In a histopathologic study of congenital hypertrophy of the retinal pigment epithelium, Wirz, Lee, and Coaker" described areas of hyperplasia and concluded that these findings could "help to explain ... the clinically documented slow growth of this malformation." We previously described some progressive changes of congenital hypertrophy of the retinal pigment epithelium.v? We undertook this study to provide a longer follow-up, in addition to some new observations in patients with such lesions.
Patients and Methods All patients with congenital hypertrophy of the retinal pigment epithelium photographed at the University Eye Clinic of Lausanne were reviewed. Patients with multifocal and bilateral lesions corresponding to congenital grouped pigmentation of the retina or familial adenomatous polyposis coli were excluded. Sixty-four patients with congenital hypertrophy of the retinal pigment epithelium seen between August 1973 and July 1990 were included in this series. There were 27 men and 37 women whose age at initial examination ranged from 7 to 72 years (mean age, 39.2 years; median age,
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38.5 years). All patients were white except for one black. All patients were asymptomatic. Changes between the first and last examinations were studied in 35 patients with more than one year of follow-up.
Scattered chorioretinal atrophic spots were seen in the same or the fellow eye in two patients and a choroidal nevus was seen in three patients. No other important ocular or systemic findings were observed. The clinical characteristics of congenital hypertrophy of the retinal pigment epithelium at first examination are summarized in Table 1. The location of the lesions was determined from the fundus photographs and the equator was defined arbitrarily as the area of the vortex veins ampullae. The lesion was preequatorial in 28 patients, postequatorial in 34 patients, and equatorial in two patients. The size ranged from V6 disk diameter to 7 disk diameters. The shape was round or oval in 24 patients and scalloped borders were observed in 40 patients. A marginal halo was noted in 49 patients (76.6%). Five lesions were totally pigmented. In 51 patients, less than 80% of the surface was depigmented, and in eight patients, the hypo-
pigmented areas involved 80% or more of the total area. Typical punched-out depigmented lacunae were seen in 36 patients. A depigmented linear streak of the retinal pigment epithelium was observed in two patients. In one patient, the linear streak was short and in contact with the congenital hypertrophy. On fluorescein angiography the streak appeared as a window defect (Fig. 1). In another patient, the linear streak was seen across the pigmented lesion. In six patients, a pigmented area located at the anterior border of the congenital hypertrophy of the retinal pigment epithelium was observed. This area was grayish and was lighter centrally, and darker peripherally. On fluorescein angiography, this area appeared hypofluorescent in the early and late phases of the angiograms (Fig. 2). In some patients, this retinal area appeared as slightly detached. In one patient, the adjacent pigmented area was detected only on fluorescein angiography. Of the 35 followed-up patients, 16 were followed up less than five years, 11 were followed up between five and ten years, and eight were followed up more than ten years. The longest follow-up was 14 years. The observed changes during the follow-up period are summarized in Table 2. An increase of the de pigmented part of the congenital hypertrophy of the retinal pigment epithelium was observed in 29 patients
TABLE 1 CLINICAL CHARACTERISTICS OF CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM AT FIRST EXAMINATION TOTALPATIENTS (N=64)
Postequatorial Equatorial Shape
Round or oval Scalloped Marginal halo Depigmentation Nearly absent < 80% of surface ",80% of surface
24 40 49
Lacunae Linear streaks of the retinal pigment epithelium Adjacent pigmented areas
Fig. 1 (Chamot, Zografos, and Klainguti). Linear streak in contact with a congenital hypertrophy of the retinal pigment epithelium. A window defect was seen on fluorescein angiography.
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Fig. 2 (Chamot, Zografos, and Klainguti). Left, A pigmented area located at the anterior border of the congenital hypertrophy of the retinal pigment epithelium. This area is grayish and is lighter centrally, and darker peripherally. Right, The whole surface of this area appears hypo fluorescent on fluorescein angiography.
(82.8%). In four of these patients, lacunae were formed for the first time. A concentric enlargement of the lesion (Fig. 3) was noted in 26 patients (74.3%) and was always associated with an increase in depigmentation. Of these 26 patients, 21 (81 %) were followed up more than three years, compared to three of the nine patients (33%) without enlargement. Ten of the patients with lesion enlargement were older than 45 years at the initial examination. Follow-up of the linear streaks was obtained in two patients. In one patient, the congenital hypertrophy of the retinal pigment epithelium and the streak remained unchanged after a follow-up period of one year nine months. The other patient, a 7-year-old boy, had a totally pigmented round lesion at the initial examination (Fig. 4). Five years later, lacunae and a marginal halo with concentric enlargement were noted. Additionally, a small linear streak parallel to the ora serrata was seen. The congenital hypertrophy, which was round at first visit, became oval. At subsequent visits, the hypopigmented part, as well as the whole lesion was enlarged. The linear streak extended circumferentially. Thirteen years after the initial examination, a second circumferential linear streak appeared more posteriorly. This second streak was less distinct than the initial one, but was evident on fluorescein angiography (Fig. 5). The contour of congenital hypertrophy changed again to round. No retinal or vitreous changes were noted. The patient denied trau-
rna. His myopia had increased from 1 diopter to 5.25 diopters at the end of the follow-up period. Three of the six patients with adjacent pigmented areas were followed up for more than one year. One patient remained unchanged. In the other two, total disappearance of the pigmented area was seen three years and four years later, respectively. In one of these two patients, the fleck reappeared three years later at the same place but with a slightly different contour (Fig. 6). In an additional patient, the adjacent lesion was present only at the second examination, after a seven-year follow-up period. This fleck was slightly more extended at subsequent examinations. TABLE 2 OBSERVED CHANGES IN 35 PATIENTS WITH CONGENITAL HYPERTROPHY OF THE RETINAL PIGMENT EPITHELIUM OBSERVED CHANGES
Increase of the depigmented part of the lesion Appearance of marginal halo Concentric enlargement Development of a linear streak of the retinal pigment epithelium
NO. OF PATIENTS (%)
29 (82.8) 1 (2.9) 26 (74.3)
Development of an adjacent pigmented area
1 (2.9) 1 (2.9)
Disappearance and reappearance of an adjacent pigmented area
Total disappearance of an adjacent pigmented area
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Fig. 3 (Chamot, Zografos, and Klainguti). Slight but obvious enlargement of a congenital hypertrophy of the retinal pigment epithelium. Left, Note that lesion does not extend to vascular crossing depicted by arrow at initial examination. Right, Note that lesion now extends as far as the vascular crossing after a seven-year follow-up period (arrow).
Discussion Solitary unilateral congenital hypertrophy of the retinal pigment epithelium was studied in 64 patients, and 35 of them were followed up for one to 14 years. Patients with multifocal lesions were excluded because those lesions were most likely different clinical entities. These lesions are either congenital grouped pigmentation of the retina (or bear tracks), which show a characteristic configuration and distribution of the pigmented lesions, or the multifocal and bilateral form of congenital hypertrophy of the retinal pigment epithelium, which many times is associated with familial adenomatous polyposis COli. 17- 21 The solitary lesions are generally not associated with systemic disease.v":" However, the lesions have been observed in two patients with polymalformative syndromes." in one patient with syringomyelia." and a possible association with neurofibromatosis was suggested.' The clinical findings at the initial examination of the 35 patients with long follow-up, including shape, location, degree of atrophy of the congenital hypertrophy, and patient age, were not different from the remaining patients and from patients of previously published reports.r" The increase of the depigmented part of the lesion has already been described. 2,3,6,7,9 In our study increased depigmentation was observed in 29 of the followed-up patients (82.8%). Norris and Cleasby" first described an increase of size of a congenital hypertrophy of the retinal pigment
epithelium over a 13-year period in a 42-yearold woman. Other patients have been subsequently described.5-7.14.15 Cass" thought that enlargement can be occasionally observed and had seen it in one patient. Our study suggests that this concentric enlargement is the rule rather than the exception and it was noted in 26 pa tients (74.3 % ). This progression may be small and may be detected only after careful
Fig. 4 (Chamot, Zografos, and Klainguti). Fluorescein angiogram of a congenital hypertrophy of the retinal pigment epithelium at initial examination of a 7-year-old boy.
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Fig. 5 (Chamot. Zografos,
and Klainguti). Composite fluorescein angiogram from the patient in Figure 4, 13 years later. Note progression of the depigmented part and concentric enlargement, along with the appearance of two streaks with window defects.
examination of serial fundus photographs (Fig. 3). The frequency of enlargement of hypertrophy depended on the length of the follow-up and it has been observed in both young and old patients. In some patients, uncommon changes have been observed. These include the presence or the appearance of linear streaks near or across the congenital hypertrophy of the retinal pigment epithelium and of pigmented areas adjacent to the anterior border of the lesion. These additional changes are rather surprising, considering the presumed congenital origin of these lesions, which is probably caused by a primary failure in the differentiation of a part of the pigment epithelium cells. 3 ,9. 1O, 16 In the first histopathologic studies, the hyperpigmented parts of congenital hypertrophy of the retinal pigment epithelium were described as a single layer of hypertrophic pigment epithelium cells that are filled with atypical pigment granules that are much larger and rounder than in normal pigment epithelium cells. 2 ,3,l 2 The pigment of the retinal pigment epithelium cells located in the surrounding clear halo area was scarce, and in the areas corresponding to the lacunae, the pigment epithelium cells, as well as the photoreceptors, were absent. Later, in 1982, Wirz, Lee, and Coaker" demonstrated the additional presence of hyperplastic and
multilaminated cells in a macroscopically typical congenital hypertrophy of the retinal pigment epithelium. These investigators concluded that at least some of these cases "may in fact represent ... a spectrum of atrophy, hypertrophy and hyperplasia" and that these "findings help to explain ... the slow growth of this malformation." The presence of hyperplasia was also supported by Lloyd and associates" in 1990. In a study of a congenital hypertrophy with light and scanning electron microscopy, Lloyd and associates" observed that cellular density was greater in the area of the lesion than in the normal adjacent pigment epithelium. They also noted that the pigment epithelium cells located in the area of the depigmented halo were elongated, with a longitudinal axis oriented parallel to the lesion's circumference. They considered these findings "highly suggestive of cellular contact inhibition occurring between the normal pigment epithelium and an expanding population of cells." Bearing in mind the reactive potential of the retinal pigment epithelium, the changes observed in congenital hypertrophy of the retinal pigment epithelium might be the result of acquired changes added to the primary congenital lesion." Conversely, these changes may result from its congenital origin. During prenatal and postnatal growth, the
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Fig. 6 (Chamot, Zografos, and Klainguti). Top left, A congenital hypertrophy of the retinal pigment epithelium with adjacent pigmented area (arrows). Top right, After a three-year follow-up period, the pigmented area disappeared. Bottom left, After a follow-up period of six years, the pigmented area reappeared with a slightly different contour from the one observed initially (arrows). Note also the enlargement of the congenital hypertrophy.
increase of the pigment epithelium surface results partly from mitotic proliferations, and partly from a flattening of the cells in the peripheral area of the pigment eptthelium.P-" In adults, pigment epithelium cells are flatter and broader (measuring up to 60 ....m in diameter) at the periph ery24.25 and higher and narrower (about 14 ....m in diameter) at the posterior pole." Cellular density of the pigment epithelium is reduced more and more with time, mainly at the periphery. Cellular density at the age of 45 years was found to be slightly less than half of that measured at the sixth fetal month." One could postulate that pigment epithelium cells of the congenital hypertrophy do not have the ability to flatten and retain their high and narrow configuration, whereas the neighboring pigment epithelium expands during growth.
This expansion of the normal neighboring pigment epithelium might lead to pressure on the congenital hypertrophy and cause microlesions in its center or at its junctions with healthy tissues. Lacunae could then be the result of such microlesions to allow a compensation for the inability of the hypertrophic pigment epithelium cells to flatten. This hypothesis is also supported by the observation that congenital hypertrophies of the retinal pigment epithelium are generally larger and more atrophic in the periphery than those at the posterior pole.':" The lacunae would provide more chances of expansion of the lesion and may explain the observed enlargement of congenital hypertrophy of the retinal pigment epithelium after 45 years of age, since the total pigment epithelium surface diminishes between the ages of 45 and
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90 years." The development of linear streaks and of pigmented areas adjacent to the lesion is difficult to explain. Although linear streaks have been described after blunt injuries and in myopic eyes, Our patients denied injury, and myopia, when present, did not exceed 5.25 diopters. The frequent and already recognized increase of the depigmented part of congenital hypertrophy of the retinal pigment epithelium was confirmed in our series (29 of the 35 patients, 82.8%). A concentric enlargement of the lesion was observed in 26 of the 35 patients (74.3%), whereas this change was previously considered as occasional. Additionally, two other new changes have been observed. The development of linear streaks was noted in the vicinity of or across some lesions. In a few patients, a pigmented area adjacent to the anterior border of the congenital hypertrophy of the retinal pigment epithelium was observed. At subsequent follow-up examinations, a pigmented area may remain unchanged, disappear, or recur. Considering the benign and congenital nature of the lesion, these various changes are surprising. Congenital hypertrophy of the retinal pigment epithelium is not always correctly diagnosed. In 1980, Shields and associates" studied 400 patients who were referred to an oncology ocular center for possible melanoma, but who were found by clinical evaluation to have pseudomelanoma. Congenital hypertrophy of the retinal pigment epithelium accounted for 38 of these patients (9.5%), thus representing the fourth most frequent pseudomelanoma in this series. It is therefore important for the ophthalmologist to become familiar with the potential changes of congenital hypertrophy of the retinal pigment epithelium and especially to remember that an increase of the surface of the pigmented lesion is not proof of a malignant tumor.
References 1. Reese, A. B., and Jones, I. S.: Benign melanomas of the retinal pigment epithelium. Am. J. Ophthalmol. 42:207, 1956. 2. Buettner, H.: Congenital hypertrophy of the retinal pigment epithelium (RPE). A non tumorous lesion. Mod. Probl. Ophthalmol. 12:528, 1974. 3. - - : Congenital hypertrophy of the retinal pigment epithelium. Am. J. Ophthalmol. 79:177, 1975.
4. Purcell, J. J., and Shields, J. A.: Hypertrophy with hyperpigmentation of the retinal pigment epithelium. Arch. Ophthalmol. 93:1122, 1975. 5. Shields, J. A.: Tumors and related lesions of the pigment epithelium. In Shields, J. A.: Diagnosis and Management of Intraocular Tumors. St. Louis, C. V. Mosby, 1983, pp. 389-400. 6. Chamot, L., and Zografos, L.: Tumeurs et pseudo-tumeurs de l'epithelium pigmentaire. J. Fr. Ophtalmol. 7:825, 1984. 7. Zografos, L., and Klainguti, G.: Les formes evolutives de l'hypertrophie congenitale de I'epithelium pigmentaire. Bull. Mem. Soc. Fr. Ophtalmol. 97:274, 1986. 8. Klainguti, G.: Hypertrophie de l'epithelium pigmentaire de la retine. Faculte de Medecine de l'Universite de Lausanne, Switzerland, 1987. Thesis. 9. Gass, J. D. M.: Focal congenital anomalies of the retinal pigment epithelium. Eye 3:1, 1989. 10. Champion, R., and Daicker, B. c.: Congenital hypertrophy of the pigment epithelium. Light microscopic and ultrastructural findings in young children. Retina 9:44, 1989. 11. Lloyd, W. c.. Eagle, R. c., Shields, J. A., Kwa, D. M., and Arbizo, V. V.: Congenital hypertrophy of the retinal pigment epithelium. Electron microscopic and morphometric observations. Ophthalmology 97:1052,1990. 12. Kurz, G. H., and Zimmerman, L. E.: Vagaries of the retinal pigment epithelium. Int. Ophthalmol. Clin. 2:441,1962. 13. Norris, J. L., and Cleasby, G. W.: An unusual case of congenital hypertrophy of the retinal pigment epithelium. Arch. Ophthalmol. 94:1910, 1976. 14. Boldrey, E. E., and Schwartz, A.: Enlargement of congenital hypertrophy of the retinal pigment epithelium. Am. J. Ophthalmol. 94:64, 1982. 15. Binaghi, M., Sabouret, c., and Coscas, G.: Extension d'une lesion d'hypertrophie congenitale de I'epithelium pigmentaire. J. Fr. Ophtalmol. 14:564,1991. 16. Wirz, K., Lee, W. R., and Coaker, T.: Progressive changes in congenital hypertrophy of the retinal pigment epithelium. An electron microscopic study. Graefes Arch. Clin. Exp. Ophthalmol. 219:214, 1982. 17. Blair, N. P., and Trempe, C. L.: Hypertrophy of the retinal pigment epithelium associated with Gardner's syndrome. Am. J. Ophthalmol. 90:661, 1980. 18. Buettner, H.: Kongenitale Hypertrophie des Pigmentepithels der Netzhaut und Gardner-Syndrom. Fortschr. Ophthalmol. 83:597, 1986. 19. Traboulsi, E. I., Krush, A. J., Gardner, E. J., Booker, S. V., Offerhaus, G. J. A., Yardley, J. H., Hamilton, S. R., Luk, G. D., Giardiello, F. M., Welsh, S. a., Hughes, J. P., and Maumenee, I. H.: Prevalence and importance of pigmented ocular fundus lesions in Gardner's syndrome. N. Engl. J. Med. 316:661, 1987. 20. Traboulsi, E. I., Maumenee, I. H., Krush, A. J., Alcorn, D., Giardiello, F. M., Burt, R. W., Hughes, J. P., and Hamilton, S. R.: Congenital hypertrophy of
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the retinal pigment epithelium predicts colorectal polyposis in Gardner's syndrome. Arch. Ophthalmol. 108:525, 1990. 21. Heinemann, M. H., Baker, R. H., Miller, H. H., and DeCosse, J. J.: Familial polyposis coli. The spectrum of ocular and other extracolonic manifestations. Graefes Arch. Clin. Exp. Ophthalmol. 229:213, 1991. 22. Tso, M. O. M., and Friedman, E.: The retinal pigment epithelium. III. Growth and development. Arch. Ophthalmol. 80:214, 1968. 23. Tso, M. O. M.: Developmental, reactive, and neoplastic proliferation of the retinal pigment epithelium. In Zinn, K. M., and Marmor, M. F. (eds.): The Retinal Pigment Epithelium. Cambridge, Harvard University Press, 1979, pp. 267-268.
24. Salzmann, M.: Das Pigmentepithel der Chorioidea. In Anatomie und Histologie des menschlichen Augapfels im Normalzustande, seine Entwicklung und sein Altern. Leipzig, F. Deuticke, 1912, p.67. 25. Hogan, M. J., Alvarado, J. A., and Weddell, J. E.: Retina. In Histology of the Human Eye. Philadelphia, W. B. Saunders, 1971, p. 405. 26. Tso, M. O. M., and Friedman, E.: The retinal pigment epithelium. I. Comparative histology. Arch. Ophthalmol. 78:641, 1967. 27. Shields, J. A., Augsburger, J. J., Brown, G. c., and Stephens, R. F.: The differential diagnosis of posterior uveal melanoma. Ophthalmology 87:518, 1980.
It is not that snake called lamia seen daily by the rustics attracting to itself
with fixed gaze, as the magnet attracts iron, the nightingale, which with mournful song hastens to her death? It is said also that the woIf has power by its look to cause men to have hoarse voices. The basilisk is said to have the power by its glance to deprive of life every living thing. The ostrich and the spider are said to hatch their eggs by looking at them. Maidens are said to have power in their eyes to attract to themselves the love of men. The fish called luino, which some name after St. Elmo, which is found off the coasts of Sardinia, is it not seen at night by the fishermen, shedding light with its two eyes over a great quantity of water, as though they were two candles? And all those fishes which come within the compass of this radiance, immediately come up to the surface of the water and turn over dead. Donald S. Strong, Leonardo on the Eye: An English Translation and Critical
Commentary of MS.D in the Bibliotheque Nationale, Paris, With Studies on Leonardo's Methodology and Theories of Optics New York, Garland Publishing, Inc., 1979, p. 303